Are ACE-inhibitors or ARB's still needed for cardiovascular prevention in high risk patients? Insights from profess and transcend.

The HOPE and EUROPA clinical studies have shown that treatment with the angiotensin-converting enzyme (ACE) inhibitors, ramipril and perindopril, may reduce the occurrence of major cardiovascular events in patients with proven atherosclerotic disease. The recently published results of the PRoFESS and TRANSCEND trials completed the much needed information concerning the use of an angiotensin receptor blocker for patients at high risk of cardiovascular events. PROFESS compared a therapy of telmisartan 80 mg daily with placebo in patients with a recent ischemic stroke. The difference in the primary outcome of first recurrent stroke was not statistically significant between telmisartan and placebo. The secondary outcome of major cardiovascular events showed a relative risk reduction (RRR) of 7% in favour of telmisartan. This tended to be significant (p = 0.06) despite a rather short follow-up period of only 28 months. In TRANSCEND 5926 patients at high risk for cardiovascular events were randomized to a treatment with telmisartan 80 mg daily or placebo for a mean duration of follow-up of 56 months. The primary composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization for heart failure showed a non-significant 8% RRR in favour of the telmisartan treated patients. The main secondary outcome of cardiovascular death and myocardial infarction or stroke as used in the HOPE trial showed a non-significant RRR of 13% in favour of telmisartan treated patients (p = 0.068 adjusted for multiplicity of comparisons). In comparing the Kaplan-Meier curves for the endpoint of major cardiovascular events used in HOPE, EUROPA, TRANSCEND and PRoFESS, the trends are similar. Results of most of the recently published trials have been neutral.This could partly be explained by major improvements in the optimal background therapy of the patients included. Nevertheless, the results of PRoFESS and TRANSCEND do not contradict the results from previous studies with theACE inhibitors ramipril and perindopril and the ARB telmisartan.

Doppler measurement of renal interlobar vein impedance index in uncomplicated and preeclamptic pregnancies.

OBJECTIVE: To define normal values of Renal interlobar vein impedance index (RIVI) throughout gestation, as a reference to RIVI in preeclampsia (PE). METHODS: Longitudinal evaluation of 20 uncomplicated pregnancies (UP) by standard renal duplex scan, every 4 weeks during pregnancy and postpartum. Comparison of RIVI between 40 PE and UP, and plotting of PE values against the normal reference range at corresponding gestation. RESULTS: In PE, RIVI is significantly higher than in UP, the difference being larger at the left side and in cases of preeclampsia remote from term. CONCLUSION: Increase of RIVI in women with PE is gestation-dependant.

Lessons from ONTARGET.

The recently published results of the ONTARGET trial shed a new light on the cardiovascular protection of patients at high risk of a cardiovascular event. Despite a number of trials looking at the efficacy of Angiotensin Converting Enzyme inhibitors (ACEis) or Angiotensin Receptor Blockers (ARBs) in the prevention of cardiovascular events in patients with specific high risk profiles, the question of the equivalence of ACEis and ARBs remained unanswered. The ONTARGET trial has shown that telmisartan 80 mg administered for a median duration of 4.5 years to patients at high risk of developing a major cardiovascular event, is equally effective to ramipril 10 mg. In addition, telmisartan was slightly better tolerated. The comparator ramipril has been chosen as it is currently the gold standard ACEi since the results of the HOPE study, in terms of the composite outcome of cardiovascular death, myocardial infarction and stroke. Moreover, ONTARGET is the first trial to test the hypothesis of superiority of adding an ARB (telmisartan 80 mg) to an ACEi (ramipril 10 mg) over the ACEi ramipril monotherapy in cardiovascular protection of the same broad range of high-risk patients. Surprisingly, despite a more pronounced blood pressure lowering, the combination of the two agents did not lead to an additional decrease in the number of events, but had significantly more side-effects compared to ramipril monotherapy. ONTARGET is a landmark study, performed according to the highest statistical and clinical standards, providing compelling evidence and clear answers to two important clinical questions.

Efficacy of atorvastatin after LDL-cholesterol-based dose selection in high risk dyslipidaemic patients: results of the target dose study.

BACKGROUND: Hypercholesterolaemia is one of the major risk factors for the development of coronary heart disease (CHD). European guidelines emphasize the importance of reducing low-density lipoprotein cholesterol (LDL-C) levels below 115 mg/dL (3.0 mmol/L) in patients with high CHD risk. OBJECTIVE: The present study evaluates whether selection of the atorvastatin starting dose based on baseline LDL-C levels and previous statin treatment status would result in an achievement of LDL-C targets without the need for up-titration. METHODS: A multicentre, prospective, open-label study conducted in Belgium. Patients were at high risk defined as either a history of CHD, another atherosclerotic disease, diabetes mellitus Type 2 or an estimated 10-year CHD risk > 20%. The primary endpoint was the proportion of patients achieving the LDL-C goal after 12 weeks of treatment. RESULTS: Overall, 96.4% of the 195 statin-naïve patients reached the LDL-C target after 12 weeks of treatment. The majority of the patients (95.4%) already reached LDL-C control at Week 6. Mean (SD) LDL-C levels decreased from 159 (25) mg/dL[(4.1 (0.6) mmol/L] to 86 (14) mg/dL [2.2 (0.4) mmol/L] after 12 weeks of treatment. Only 4.6% of the patients needed an up-titration at Week 6. CONCLUSIONS: Taken together, the results demonstrate that LDL-C based dose selection of atorvastatin is highly efficacious for rapid achievement of target LDL-C levels with a low need for up-titration. Application of this flexible first dosing strategy in general practice will, based on available evidence, increase adherence to atorvastatin treatment in patients with high CHD risk.

Randomized double-blind safety study of enoxaparin versus unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes treated with tirofiban and aspirin: the ACUTE II study. The Antithrombotic Combination Using Tirofiban and Enoxaparin.

BACKGROUND: In comparison with treatment with unfractionated heparin (UFH) and aspirin (ASA), both tirofiban administered with UFH and ASA, and enoxaparin plus ASA have shown superiority in reducing cardiac ischemic events in patients with unstable angina and non-ST-segment elevation myocardial infarction. Replacing UFH with enoxaparin when tirofiban is administered to patients may offer further therapeutic benefit, but could also increase bleeding. OBJECTIVE: Our objective was to provide estimates of the frequency of bleeding complications, as defined by means of the Thrombolysis In Myocardial Infarction(TIMI) group, and collect data on clinical efficacy of the combination of tirofiban with enoxaparin plus ASA. METHODS: Five hundred twenty-five patients with UA/NSTEMI were treated with tirofiban coadministered with ASA and randomized to receive either UFH (n = 210) or enoxaparin (n = 315). Therapy was administered for 24 to 96 hours. Bleeding incidences were assessed until 24 hours after trial therapy was discontinued; other clinical outcomes were assessed for as long as 30 days. RESULTS: The total bleeding rate (TIMI major + minor + loss-no-site) for the UFH group versus the enoxaparin group was 4.8% vs 3.5% (odds ratio [OR] 1.4, CI 0.6-3.4). The TIMI major and minor bleeding rates for the UFH versus the enoxaparin groups were 1.0% versus 0.3% (OR 3.0, CI 0.3-33.8) and 4.3% versus 2.5% (OR 1.7, CI 0.7-4.6). There was an increase in nuisance cutaneous and oral bleeds (<50 mL of blood loss) in the enoxaparin group. Death or myocardial infarction occurred with similar frequency in the 2 groups (9.0% vs 9.2%). However, refractory ischemia requiring urgent revascularization and rehospitalization because of unstable angina occurred more frequently in the UFH group (4.3% vs 0.6% and 7.1% vs 1.6%, respectively). CONCLUSIONS: Combination therapy with tirofiban plus enoxaparin appears safe, relative to therapy with tirofiban plus UFH.

Evaluation of glucose tolerance during treatment with celiprolol in patients with mild arterial hypertension without diabetes mellitus. The Genker General Practitioners.

A prospective evaluation of the metabolic effects of Celiprolol, a third generation Beta-Blocking agent was done by 10 general practitioners in 45 mildly hypertensive patients. (diastolic blood pressure > or = 95 mm/Hg and < or = 115 mm/Hg. In 43 patients with complete data, blood pressure and resting heart rate decreased significantly after treatment, but weight and metabolic parameters were unchanged. After 6 months therapy the 22 patients with an impaired glucose tolerance test (IGTT) had a significant decrease in plasma glucose and insulin values, and a tendency for increased HDL. These favorable metabolic effects of Celiprolol in mildly hypertensive patients with an abnormal GTT are different from the findings with other beta-blockers and justify further study.

Verapamil as prophylactic treatment for atrial fibrillation after lung operations.

BACKGROUND: Atrial fibrillation is a frequently occurring arrhythmia after thoracic operations. Preventive strategies for this complication have been extensively evaluated after cardiac operations. METHODS: We performed a prospective, open randomized study, comparing intravenous verapamil and placebo in 199 patients after pneumonectomy or lobectomy at the University Hospital of Leuven. Verapamil was administered as a bolus of 10 mg over 2 minutes followed by a 30-minute infusion of 0.375 mg/min and then 0.125 mg/min for 3 days. The patients were continuously monitored in the postoperative intensive care unit. RESULTS: Atrial fibrillation occurred in 15% of the patients receiving placebo and in 8% of the patients receiving verapamil (difference not significant). The verapamil infusion was interrupted in 9% of the patients because of bradycardia and in 14% because of hypotension. CONCLUSIONS: If tolerated, continuous intravenous verapamil infusion showed only a modest prophylactic efficacy for the occurrence of atrial fibrillation after lung operations. In the dose employed the verapamil infusion was accompanied with a high incidence of side effects necessitating interruption of the therapy.

Efficacy and safety of the 200-300 mg sustained release formulation of diltiazem administered once daily in patients with stable angina.

The aim of this multicentre randomised double blind study was to compare the efficacy and safety of the 200-300 mg sustained release diltiazem formulation administered once daily (200-300 SR) with standard diltiazem (D) given three or four times daily to patients with stable angina. Patients aged 59 years, with a reproducible exercise test on placebo, were randomised to 4 weeks of treatment with 200-300 SR (n = 70) or D (n = 74). The initial dosage was 200 mg in the 200-300 SR group and 60 mg t.i.d. in the D group, increased to 300 mg once daily or 60 mg q.i.d., respectively, if ergometric parameters, which were always measured at the end of the dosing period, had not improved after two weeks. After 4 weeks of treatment, the antianginal efficacy at rest was comparable in the 200-300 SR and the D group; there was a prolongation of the total duration of exertion of 14% and 18% respectively (P < 0.01 vs placebo for both groups with no intergroup difference). A dose-effect relation was found with both formulations. The 200-300 SR formulation gave full 24 hour anti-ischaemic protection when administered once daily. Its efficacy and safety were comparable to those of standard diltiazem t.i.d. or q.i.d. in patients with stable angina. The once daily administration should improve treatment compliance.

Amiodarone and the development of ARDS after lung surgery.

An evaluation of amiodarone as prophylactic treatment for supraventricular tachyarrhythmias after pulmonary surgery was stopped because of a high incidence of the adult respiratory distress syndrome (ARDS) after a pneumonectomy. Retrospective analysis of all cases of resection for pulmonary neoplasm in our hospital between 1987 and 1991 indicates that amiodarone may be implicated in the development of ARDS after lung surgery.

Acute pulmonary oedema in patients with primary pulmonary hypertension and normal pulmonary capillary wedge pressure.

Acute pulmonary oedema with normal pulmonary capillary wedge pressure, occurred in 2 patients with primary pulmonary hypertension, probably due to venoocclusive diseases. In both cases an increase in cardiac output induced by vasodilator therapy with a calcium antagonist or a viral infection with fever lead to an increase in hydrostatic pulmonary capillary pressure which was not identical to the pulmonary capillary wedge pressure.

Acute haemodynamic effects of lisinopril and captopril in patients with severe congestive heart failure.

The acute haemodynamic effects of several equivalent dosages of lisinopril and captopril were compared in patients with severe class III or IV congestive heart failure. The evaluation was started with a low dose of 2.5 mg lisinopril o.d. or 6.25 mg captopril t.i.d. and subsequent daily increases to 5 and 10 mg lisinopril o.d. or 12.5 and 25 mg captopril t.i.d. Captopril had an earlier onset of action compared to lisinopril and caused larger diurnal fluctuations of the haemodynamic parameters. Lisinopril provoked a more pronounced decrease in pulmonary capillary wedge pressure (PCWP) than captopril and only lisinopril increased the cardiac index significantly. Side-effects of hypotension or increase in serum creatinine leading to withdrawal according to protocol were noted in 3 patients on each drug. Increases in dosage caused very little increase in haemodynamic effect, suggesting that complete suppression of the angiotensin-converting enzyme may not be necessary for an optimal clinical response.

Comparison of the effect of celiprolol and nifedipine on blood pressure and plasma lipids.

During a double-blind, randomized study in hypertensive patients, changes in blood pressure (BP) and in plasma lipid and lipoprotein levels during treatment with celiprolol were compared with those occurring during nifedipine treatment. Fifty-three patients (28 men and 25 women) with mild-to-moderate hypertension, aged 20-64 years, were studied. After a 1-month placebo run-in period, patients were randomly assigned to receive either nifedipine (40 mg daily) or celiprolol (200 mg daily) each time using a double dummy technique. After 6 weeks, dosages of each drug could be doubled. Both drugs caused similar reductions in blood pressure but after 12 weeks treatment, the percentage of decrease in diastolic BP (DBP) was more pronounced (p less than 0.01) in the nifedipine group (-18%) than in the celiprolol group (-12%). After 6 weeks, there were no differences in plasma lipids between the two treatment groups. However, the changes after 12 weeks treatment were different (p less than 0.05) between the groups, leading to lower levels of plasma esterified cholesterol, low-density lipoprotein (LDL) cholesterol and apoprotein AI, AII, and B in the celiprolol group. Plasma lecithin cholesterol acyltransferase activity (LCAT) was not modified, suggesting that reverse cholesterol transport was not affected by the drugs. In both treatment groups, a significant positive relationship was observed between changes in LDL cholesterol and apoprotein B. As compared with nifedipine, celiprolol after 12-week therapy had a rather favorable plasma lipid profile. The clinical relevance of such findings, in terms of prevention of cardiovascular complications, has yet to be established.

Evaluation of the safety and efficacy of amrinone in chronic obstructive lung disease with cor pulmonale.

In a pilot study the effect of a bolus dose of amrinone intravenously (IV), 0.5 or 1 mg/kg body weight, in 10 patients with chronic obstructive lung disease and cor pulmonale was evaluated. We found that the higher dose of 1.0 mg/kg IV significantly (P less than 0.05) decreased the mean pulmonary artery pressure and pulmonary wedge pressure without significant changes in cardiac output, in systemic blood pressure or in arterial blood gas values. No adverse effects were recorded in any of the patients.

Intermittent dobutamine infusion in severe chronic heart failure in elderly patients.

We describe the short- and long-term haemodynamic evolution of an elderly patient with severe intractable heart failure, who was treated with intermitted dobutamine infusion. This therapeutic regimen improved haemodynamic parameters and clinical status (New York Heart Association Functional Class) and prevented the hazardous cardiac, pulmonary and psychiatric disturbances the patient had suffered from with the previous therapeutic approach. No major side-effects were noted, except for a transient drop in arterial blood pressure. Subsequently, 9 other elderly patients were treated successfully with the same protocol. We propose the intermittent use of dobutamine in elderly patients with intractable heart failure, as a useful therapy for the improvement of their cardiac condition and general well-being.

Cardiopulmonary function after lobectomy or pneumonectomy for pulmonary neoplasm.

Resection of pulmonary tissue for bronchial carcinoma causes a decrease in vital capacity of 15% after lobectomy and 35-40% following pneumonectomy. After operation the lung becomes stiffer and elastic recoil pressure and transdiaphragmatic pressure at TLC increase. Maximum effort tolerance decreases after pneumonectomy with a normal pulmonary artery pressure at rest and an increase in pulmonary artery pressure and in pulmonary vascular resistance on effort, compared to preoperative values. Cardiac output and stroke volume during effort show a decrease after operation with an increase in peripheral arterial blood pressure and in peripheral vascular resistance. Arterial oxygen saturation on effort decreases after pneumonectomy, possibly due to the absolute decrease in diffusing capacity. When comparing resting and exercise values at identical work loads, increases in systemic arterial blood pressure, pulmonary and systemic vascular resistance and arteriovenous oxygen difference were similar although generally less pronounced after lobectomy compared to pneumonectomy; cardiac output, stroke volume and oxygen consumption showed the same tendency to decrease after lobectomy and pneumonectomy.